21-Alkoxy-pregnane compounds possessing significant antiprogestogen activity were first described in the patent applications No. WO97041145 and WO01074840. Telapristone acetate (CDB-4124) is this type of compound, which is currently under clinical development in Phase III studies. According to the results published so far it is exceptionally promising for the treatment of uterine fibroma (a benign tumor of connective tissue).
The synthesis of 21-methoxy-pregnane derivatives of formula (I) was first described in the patent application No. WO97041145 (see Figure 1.).
The synthesis of compound of formula (I) (R=dimethylamino group) was carried out the following way:

First the side-chain in position 17 was introduced, then the obtained compound was substituted in position 11 by Grignard reaction.
The hydroxyl group in position 17 of the commercially available 3,3-[1,2-ethanediyl-bis-(oxy)]-17α-hydroxy-estr-5(10),9(11)-dien-17β-carbonitrile was silylated with (bromomethyl)dimethylsilyl chloride. Then the 17-silyloxy bromo compound was transformed into 21-bromo compound using lithium diisopropylamide at −78° C. Introduction of the methoxy group in position 21 was carried out in a rather complicated, multistep process: via the 21-acetoxy and 21-hydroxy derivatives, using 6 equivalent excess of trimethyloxonium tetrafluoroborate salt together with proton sponge (SNAP reaction). On one hand this method is expensive, on the other hand the removal of the proton sponge is difficult, in many cases it requires the purification of the product in several steps.
Further disadvantage of the process is that the epoxide needed for the Grignard reaction is synthesized in the 7th step. This is not economical, because during the epoxide formation four isomers of the epoxide are formed according to NMR spectroscopy.
The synthesis, which is identical with the above mentioned one, of compound of formula (I) (R=acetyl) is described in the patent application No. WO01074840.
A partly different synthesis is described in the patent application No. WO01047945. In this case also the side-chain in position 17 was formed, then the substituent in position 11 was introduced by Grignard reaction. In this process the synthesis of the epoxide was also carried out in the advanced phase of the reaction sequence. Introduction of the methoxy group in position 21 was carried out as described in the previous patent applications.
An industrial process is described in the patent application No. WO2009001148 (Figure 2.). The difference between this process and the previously described ones is that first the substituent in position 11 was introduced, then the side-chain in position 17 was formed. The advantage of this process is that the epoxide formation is carried out at the beginning of the reaction sequence, this results in less loss of material as compared to the previously described ones. During the formation of the side-chain in position 17 the carbonitrile was transformed into carbaldehyde by reduction. The obtained carbaldehyde was methoxymethylated in Grignard reaction. Then the oxidation of the hydroxyl group in position 20 was carried out to yield the compound of formula (II), which was acylated. Introduction of the methoxy group was carried out in less steps as compared to the previously described processes, but during the Grignard reaction a mercury compound was used, which is not easily manageable from the point of environmental protection.

The synthesis of methoxymethyl lithium reagent was first described in 1964 in a publication (Tetrahedron Letters (1964), 24, 1503-6). Lithium was reacted with methoxymethyl chloride in methylal at (−25)-(−30)° C. The so obtained solution of the reagent was reacted with carbonyl group containing compounds (ketones, aldehydes and carboxylic acid esters) and this way alcohols containing methoxymethyl group were synthesized.
Similar process was described in 1967 (Liebigs Ann. Chem. 704, 120-125 (1967)). According to this publication the reagent was used in similar reactions.
In 1996 a process was described in a publication (Tetrahedron 52(5), 1643-1650, (1996)) for the in situ synthesis of ethoxymethyl lithium from chloromethyl ethyl ether and lithium in the presence of 4,4′-di-tert-butylbiphenyl catalyst in tetrahydrofuran at −90° C., which was reacted with compounds containing carbonyl group or with benzonitrile.
Alkoxymethyl lithium reagent has not been used so far in the synthesis of steroids.